APPLICANT'S ABSTRACT: The major goal of this research is to explore whether a net dysfunction of the central noradrenergic system physiology occurs after a paradigm of chronic cocaine administration. A research plan will be developed to study changes in locus coeruleus (LC) function and norepinephrine (NE) neuromodulatory actions in the somatosensory and cerebellar cortices after repeated cocaine administration. An initial series of investigations will examine several parameters of LC physiology in terms of spontaneous LC firing rate and patterns of activity, and in changes in alpha-2-receptor sensitivity to agonists and antagonists compounds. In addition, studies will also investigate alterations in the behavior of LC responses to sensory evoked discharges and iontophoretically-induced excitation by the release of putative neurotransmitters that supposedly mediate LC reaction to sensory stimulation. We hypothesized that cocaine, by virtue of its ability to increase synaptic level of NE or other independent actions, can alter LC neuron activity and thus the input/output relationship of NE cells. A second series of studies will examine changes in NE modulatory actions in the somatosensory and cerebellar cortices, two target structures of LC noradrenergic innervation. Experiments using microiontophoresis application of putative neurotransmitters glutamate, GABA and acetylcholine together with peripheral and central nervous system stimulation procedures will be employed to quantitatively assess the NE modulatory actions on synaptic efficacy within the aforementioned brain circuits. The purpose of these experiments is to identify possible alterations in NE neuromodulatory actions which might form part of the neural substrates responsible for cocaine's psychostimulant effects. Finally, the "in vitro" receptor autoradiography technique will be employed to measure the relative distribution of alpha-2 receptors in the LC in an effort to observe any changes in this important receptor that control normal LC physiology. Overall, this approach is aimed at developing a comprehensive understanding of the effects of chronic cocaine administration on CNS noradrenergic physiology which might form part of the basis of cocaine's addiction.